Drug-protein adducts based on covalent bonds are necessary to stimulate the immune system.
To initiate an IgE-immune response to a small drug-like a beta-lactam, a complex interplay of antigen-presenting cells (APC), T cells and B cells takes place (1,7). Neither the drug itself (too small) or the protein (often a self protein, to which tolerance exists) elicit a reaction. It is the novel hapten-protein adduct, which represents the antigen, which stimulates B- and T cells. For T-cell stimulation, the hapten-protein adduct is processed inside APC into smaller peptides and then presented on HLA. These immunogenic peptides keep the drug bound to the amino-acid only if the bonds between peptide and drug are covalent and stable.
For instance, amoxicilloyl- albumin is taken up by dendritic cells (DC) and/or B-cells acting as APCs. This hapten-protein adduct is processed inside the APC to peptides. Due to the covalent link between the hapten and protein/peptide, the peptides resulting from processing and presented to T cells still carry the amoxicilloyl group. A non-covalent bond between drug and protein would be disrupted by intracellular processing. This presentation of new (drug- modified) peptides stimulates T-cells, which secrete IL-4/IL-13 to provide help for B-cell maturation into IgE-producing plasma cells. The secreted specific IgE binds immediately to the high affinity Fc-receptor for IgE (FcεRI) on mast cells (MC) and basophils the individual is sensitized (figure 3). But even if therapy is continued, no symptoms appear.